brain facts a primer on the brain and nervous system - the society for neuroscience

Brain Facts
A PRIMER ON THE BR AIN AND NERVOUS SYSTEM

THE SOCIET Y FOR NEUROSCIENCE


Brain Facts
A PRIMER ON THE BR AIN AND NERVOUS SYSTEM

THE SOCIET Y FOR NEUROSCIENCE


THE SOCIETY FOR NEUROSCIENCE

The Society for Neuroscience is the world’s largest organization of scientists and physicians dedicated to understanding the brain, spinal cord
and peripheral nervous system.
Neuroscientists investigate the molecular and cellular levels of the
nervous system; the neuronal systems responsible for sensory and
motor function; and the basis of higher order processes, such as cognition and emotion. This research provides the basis for understanding the medical fields that are concerned with treating nervous system
disorders. These medical specialties include neurology, neurosurgery,
psychiatry and ophthalmology.
Founded in 1970, the Society has grown from 500 charter members
to more than 29,000 members. Regular members are residents of Canada,
Mexico and the United States—where more than 100 chapters organize
local activities. The Society’s membership also includes many scientists
from throughout the world, particularly Europe and Asia.
The purposes of the Society are to:
∫ Advance the understanding of the nervous system by bringing together
scientists from various backgrounds and by encouraging research in all
aspects of neuroscience.
∫ Promote education in the neurosciences.

∫ Inform the public about the results and implications of new research.
The exchange of scientific information occurs at an annual fall
meeting that presents more than 14,000 reports of new scientific
findings and includes more than 25,000 participants. This meeting, the
largest of its kind in the world, is the arena for the presentation of new
results in neuroscience.
The Society’s bimonthly journal, The Journal of Neuroscience, contains articles spanning the entire range of neuroscience research and
has subscribers worldwide. A series of courses, workshops and symposia held at the annual meeting promote the education of Society
members. The Neuroscience Newsletter informs members about Society
activities.
A major mission of the Society is to inform the public about the
progress and benefits of neuroscience research. The Society provides
information about neuroscience to school teachers and encourages its
members to speak to young people about the human brain and nervous
system.


Brain Facts

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
THE NEURON . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Neurotransmitters ∫ Second Messengers
BRAIN DEVELOPMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Birth of Neurons and Brain Wiring ∫ Paring Back ∫ Critical Periods
SENSATION AND PERCEPTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Vision ∫ Hearing ∫ Taste and Smell ∫ Touch and Pain
LEARNING AND MEMORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

MOVEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
SLEEP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

The Stu∑ of Sleep ∫ Sleep Disorders ∫ How is Sleep Regulated?
STRESS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

The Immediate Response ∫ Chronic Stress
AGING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Aging Neurons ∫ Intellectual Capacity
ADVANCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Parkinson’s Disease ∫ Pain ∫ Epilepsy ∫ Major Depression
Manic-Depressive Illness
CHALLENGES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Addiction ∫ Alzheimer’s Disease ∫ Learning Disorders
Stroke ∫ Neurological Trauma ∫ Anxiety Disorders
Schizophrenia ∫ Neurological AIDS ∫ Multiple Sclerosis
Down Syndrome ∫ Huntington’s Disease ∫ Tourette Syndrome
Brain Tumors ∫ Amyotrophic Lateral Sclerosis
NEW DIAGNOSTIC METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Imaging Techniques ∫ Gene Diagnosis
POTENTIAL THERAPIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

New Drugs ∫ Trophic Factors ∫ Cell and Gene Therapy
GLOSSARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Introduction

I

t sets humans apart from all other species by allowing us
to achieve the wonders of walking on the moon and composing masterpieces of literature, art and music. Throughout recorded time, the human brain—a spongy, threepound mass of fatty tissue—has been compared to a
telephone switchboard and a supercomputer.
But the brain is much more complicated than any of these
devices, a fact scientists confirm almost daily with each new
discovery. The extent of the brain’s capabilities is unknown, but
it is the most complex living structure known in the universe.
This single organ controls all body activities, ranging from
heart rate and sexual function to emotion, learning and memory. The brain is even thought to influence the response to disease of the immune system and to determine, in part, how well
people respond to medical treatments. Ultimately, it shapes our
thoughts, hopes, dreams and imagination. In short, the brain is
what makes us human.
Neuroscientists have the daunting task of deciphering the
mystery of this most complex of all machines: how as many as
a trillion nerve cells are produced, grow and organize themselves into e∑ective, functionally active systems that ordinarily
remain in working order throughout a person’s lifetime.
The motivation of researchers is twofold: to understand
human behavior better—from how we learn to why people
have trouble getting along together—and to discover ways to
prevent or cure many devastating brain disorders.
The more than 1,000 disorders of the brain and nervous
system result in more hospitalizations than any other disease
group, including heart disease and cancer. Neurological illnesses
a∑ect more than 50 million Americans annually at costs exceeding $400 billion. In addition, mental disorders, excluding drug
and alcohol problems, strike 44 million adults a year at a cost

of some $148 billion.
However, during the congressionally designated Decade of
the Brain, which ended in 2000, neuroscience made significant
discoveries in these areas:
∫ Genetics. Key disease genes were identified that underlie several neurodegenerative disorders—including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and amyotrophic
lateral sclerosis. This has provided new insights into underlying
2

disease mechanisms and is beginning to suggest new treatments.
With the mapping of the human genome, neuroscientists
will be able to make more rapid progress in identifying genes that
either contribute to human neurological disease or that directly
cause disease. Mapping animal genomes will aid the search for
genes that regulate and control many complex behaviors.
∫ Brain Plasticity. Scientists began to uncover the molecular
bases of neural plasticity, revealing how learning and memory
occur and how declines might be reversed. It also is leading to
new approaches to the treatment of chronic pain.
∫ New Drugs. Researchers gained new insights into the mechanisms of molecular neuropharmacology, which provides a new
understanding of the mechanisms of addiction. These advances
also have led to new treatments for depression and obsessivecompulsive disorder.
∫ Imaging. Revolutionary imaging techniques, including magnetic resonance imaging and positron emission tomography,
now reveal brain systems underlying attention, memory and
emotions and indicate dynamic changes that occur in schizophrenia.
∫ Cell Death. The discovery of how and why neurons die, as
well as the discovery of stem cells, which divide and form new
neurons, has many clinical applications. This has dramatically
improved the outlook for reversing the e∑ects of injury both in
the brain and spinal cord. The first e∑ective treatments for
stroke and spinal cord injury based on these advances have been

brought to clinical practice.
∫ Brain Development. New principles and molecules responsible for guiding nervous system development now give scientists a better understanding of certain disorders of childhood.
Together with the discovery of stem cells, these advances are
pointing to novel strategies for helping the brain or spinal cord
regain functions lost to diseases.
Federal neuroscience research funding of more than $4 billion annually and private support should vastly expand our
knowledge of the brain in the years ahead.
This book only provides a glimpse of what is known about
the nervous system, the disorders of the brain and some of the
exciting avenues of research that promise new therapies for
many neurological diseases.


THE BRAIN. Cerebral cortex
(above). This part of the brain is
divided into four sections: the
Motor cortex

Sensory cortex

occipital lobe, the temporal
lobe, the parietal lobe and the

Frontal lobe

frontal lobe. Functions, such as

Parietal lobe

vision, hearing and speech, are

distributed in selected regions.
Some regions are associated
Occipital lobe

with more than one function.
Major internal structures
(below). The (1) forebrain is

Temporal lobe

credited with the highest intellectual functions—thinking,
planning and problem-solving.
The hippocampus is involved in
memory. The thalamus serves as
a relay station for almost all of

Cerebrum

the information coming into the

Thalamus

brain. Neurons in the hypothalamus serve as relay stations for

Hypothalamus

internal regulatory systems by
monitoring information coming
1 Forebrain

in from the autonomic nervous
system and commanding the
body through those nerves and
Amygdala

the pituitary gland. On the
Hippocampus

upper surface of the (2) midbrain are two pairs of small

2 Midbrain
Pons
3 Hindbrain

hills, colliculi, collections of

Cerebellum

Spinal cord

cells that relay specific sensory

Medulla
oblongata

information from sense organs
to the brain. The (3) hindbrain
consists of the pons and
medulla oblongata, which help
control respiration and heart

rhythms, and the cerebellum,

THE TOLL OF SELECTED BRAIN AND NERVOUS SYSTEM DISORDERS*

which helps control movement

Condition

Total Cases

Costs Per Year

28 million

$ 56 billion

18.8 million

$ 44 billion

Alzheimer’s Disease

4 million

$ 100 billion

Stroke

4 million

$ 30 billion

Schizophrenia

3 million

$ 32.5 billion

1.5 million

$ 15 billion

Traumatic Head Injury

1 million

$ 48.3 billion

Multiple Sclerosis

350,000

$ 7 billion

Spinal Cord Injury

250,000

$ 10 billion

Hearing Loss
All Depressive Disorders

Parkinson’s Disease

as well as cognitive processes
that require precise timing.

* Estimates provided by the National Institutes of Health and voluntary organizations.

3


The Neuron

A

specialized cell designed to transmit information to other nerve cells, muscle or gland
cells, the neuron is the basic working unit of
the brain. The brain is what it is because of
the structural and functional properties of
neurons. The brain contains between one billion and one trillion neurons.
The neuron consists of a cell body containing the nucleus
and an electricity-conducting fiber, the axon, which also gives
rise to many smaller axon branches before ending at nerve terminals. Synapses, from the Greek words meaning to “clasp
together,” are the contact points where one neuron communicates with another. Other cell processes, dendrites, Greek for
the branches of a tree, extend from the neuron cell body and
receive messages from other neurons. The dendrites and cell
body are covered with synapses formed by the ends of axons of
other neurons.

Neurons signal by transmitting electrical impulses along
their axons that can range in length from a tiny fraction of an
inch to three or more feet. Many axons are covered with a layered insulating myelin sheath, made of specialized cells, that
speeds the transmission of electrical signals along the axon.
Nerve impulses involve the opening and closing of ion channels, water-filled molecular tunnels that pass through the cell
membrane and allow ions—electrically charged atoms—or
small molecules to enter or leave the cell. The flow of these ions
creates an electrical current that produces tiny voltage changes
across the membrane.
The ability of a neuron to fire depends on a small difference in electrical charge between the inside and outside of
the cell. When a nerve impulse begins, a dramatic reversal
occurs at one point on the cell’s membrane. The change, called
an action potential, then passes along the membrane of the axon
at speeds up to several hundred miles an hour. In this way, a
neuron may be able to fire impulses scores or even hundreds
of times every second.
On reaching the ends of an axon, these voltage changes
trigger the release of neurotransmitters, chemical messengers.
Neurotransmitters are released at nerve ending terminals and
4

bind to receptors on the surface of the target neuron.
These receptors act as on and o∑ switches for the next cell.
Each receptor has a distinctly shaped part that exactly matches
a particular chemical messenger. A neurotransmitter fits into
this region in much the same way as a key fits into an automobile ignition. And when it does, it alters the neuron’s outer
membrane and triggers a change, such as the contraction of a
muscle or increased activity of an enzyme in the cell.
Knowledge of neurotransmitters in the brain and the action
of drugs on these chemicals—gained largely through the study

of animals—is one of the largest fields in neuroscience. Armed
with this information, scientists hope to understand the circuits
responsible for disorders such as Alzheimer’s disease and Parkinson’s disease. Sorting out the various chemical circuits is vital
to understanding how the brain stores memories, why sex is such
a powerful motivation and what is the biological basis of mental illness.

Neurotransmitters
Acetylcholine The first neurotransmitter to be identified 70
years ago, was acetylcholine (ACh). This chemical is released
by neurons connected to voluntary muscles (causing them to
contract) and by neurons that control the heartbeat. ACh also
serves as a transmitter in many regions of the brain.
ACh is formed at the axon terminals. When an action
potential arrives at the terminal, the electrically charged calcium ion rushes in, and ACh is released into the synapse and
attaches to ACh receptors. In voluntary muscles, this opens
sodium channels and causes the muscle to contract. ACh is
then broken down and re-synthesized in the nerve terminal.
Antibodies that block the receptor for ACh cause myasthenia
gravis, a disease characterized by fatigue and muscle weakness.
Much less is known about ACh in the brain. Recent discoveries suggest, however, that it may be critical for normal
attention, memory and sleep. Since ACh-releasing neurons die
in Alzheimer’s patients, finding ways to restore this neurotransmitter is one goal of current research.
Amino Acids Certain amino acids, widely distributed
throughout the body and the brain, serve as the building blocks


of proteins. However, it is now apparent that certain amino
acids can also serve as neurotransmitters in the brain.
The neurotransmitters glutamate and aspartate act as excitatory signals. Glycine and gamma-aminobutyric acid (GABA)
inhibit the firing of neurons. The activity of GABA is increased

by benzodiazepine (Valium) and by anticonvulsant drugs. In
Huntington’s disease, a hereditary disorder that begins during
mid-life, the GABA-producing neurons in the brain centers
coordinating movement degenerate, thereby causing incontrollable movements.

Glutamate or aspartate activate N-methyl-D-aspartate
(NMDA) receptors, which have been implicated in activities
ranging from learning and memory to development and specification of nerve contacts in a developing animal. The stimulation of NMDA receptors may promote beneficial changes in
the brain, whereas overstimulation can cause nerve cell damage
or cell death in trauma and stroke.
Key questions remain about this receptor’s precise structure,
regulation, location and function. For example, developing
drugs to block or stimulate activity at NMDA receptors holds
NEURON. A neuron fires by
transmitting electrical signals
along its axon. When signals
reach the end of the axon, they
trigger the release of neurotransmitters that are stored in

Dendrites

pouches called vesicles. Neurotransmitters bind to receptor
molecules that are present on
Nucleus

the surfaces of adjacent neurons. The point of virtual contact
is known as the synapse.

Cell body

Axon
Myelin sheath

Nerve impulse

Axon

Vesicle

Synapse

Direction
of impulse

Axon
terminals

Dendrite
of receiving
neuron

Neurotransmitters
Receptor molecules

5


promise for improving brain function and treating neurological disorders. But this work is still in the early stage.
Catecholamines Dopamine and norepinephrine are widely
present in the brain and peripheral nervous system. Dopamine,

which is present in three circuits in the brain, controls movement, causes psychiatric symptoms such as psychosis and regulates hormonal responses.
The dopamine circuit that regulates movement has been
directly related to disease. The brains of people with Parkinson’s
disease—with symptoms of muscle tremors, rigidity and
di≈culty in moving—have practically no dopamine. Thus,
medical scientists found that the administration of levodopa, a
substance from which dopamine is synthesized, is an e∑ective
treatment for Parkinson’s, allowing patients to walk and perform skilled movements successfully.
Another dopamine circuit is thought to be important for
cognition and emotion; abnormalities in this system have been
implicated in schizophrenia. Because drugs that block dopamine
receptors in the brain are helpful in diminishing psychotic
symptoms, learning more about dopamine is important to
understanding mental illness.
In a third circuit, dopamine regulates the endocrine system. It directs the hypothalamus to manufacture hormones and
hold them in the pituitary gland for release into the bloodstream, or to trigger the release of hormones held within cells
in the pituitary.
Nerve fibers containing norepinephrine are present throughout the brain. Deficiencies in this transmitter occur in patients
with Alzheimer’s disease, Parkinson’s disease and those with
Korsako∑’s syndrome, a cognitive disorder associated with chronic
alcoholism. Thus, researchers believe norepinephrine may play
a role in both learning and memory. Norepinephrine also is
secreted by the sympathetic nervous system in the periphery to
regulate heart rate and blood pressure. Acute stress increases
the release of norepinephrine.
Serotonin This neurotransmitter is present in many tissues,
particularly blood platelets and the lining of the digestive tract
and the brain. Serotonin was first thought to be involved in
high blood pressure because it is present in blood and induces
a very powerful contraction of smooth muscles. In the brain, it

has been implicated in sleep, mood, depression and anxiety.
Because serotonin controls the di∑erent switches a∑ecting various emotional states, scientists believe these switches can be
manipulated by analogs, chemicals with molecular structures
similar to serotonin. Drugs that alter serotonin’s action, such as
fluoxetine (Prozac), have relieved symptoms of depression and
obsessive-compulsive disorder.
Peptides These chains of amino acids linked together, have
been studied as neurotransmitters only in recent years. Brain
peptides called opioids act like opium to kill pain or cause sleepiness. (Peptides di∑er from proteins, which are much larger and
6

more complex combinations of amino acids.)
In 1973, scientists discovered receptors for opiates on neurons in several regions in the brain that suggested the brain
must make substances very similar to opium. Shortly thereafter,
scientists made their first discovery of an opiate produced by
the brain that resembles morphine, an opium derivative used
medically to kill pain. They named it enkephalin, literally meaning “in the head.” Subsequently, other opiates known as endorphins—from endogenous morphine—were discovered.
The precise role of the opioids in the body is unclear. A
plausible guess is that enkephalins are released by brain neurons
in times of stress to minimize pain and enhance adaptive behavior. The presence of enkephalins may explain, for example, why
injuries received during the stress of combat often are not
noticed until hours later.
Opioids and their receptors are closely associated with pathways in the brain that are activated by painful or tissue-damaging stimuli. These signals are transmitted to the central nervous
system—the brain and spinal cord—by special sensory nerves,
small myelinated fibers and tiny unmyelinated or C fibers.
Scientists have discovered that some C fibers contain a peptide called substance P that causes the sensation of burning pain.
The active component of chili peppers, capsaicin, causes the
release of substance P.
Trophic factors Researchers have discovered several small
proteins in the brain that are necessary for the development,

function and survival of specific groups of neurons. These small
proteins are made in brain cells, released locally in the brain,
and bind to receptors expressed by specific neurons. Researchers
also have identified genes that code for receptors and are
involved in the signaling mechanisms of trophic factors. These
findings are expected to result in a greater understanding of
how trophic factors work in the brain. This information also
should prove useful for the design of new therapies for brain
disorders of development and for degenerative diseases, including Alzheimer’s disease and Parkinson’s disease.
Hormones After the nervous system, the endocrine system
is the second great communication system of the body. The
pancreas, kidney, heart and adrenal gland are sources of hormones. The endocrine system works in large part through the
pituitary that secretes hormones into the blood. Because endorphins are released from the pituitary gland into the bloodstream, they might also function as endocrine hormones. Hormones activate specific receptors in target organs that release
other hormones into the blood, which then act on other tissues,
the pituitary itself and the brain. This system is very important
for the activation and control of basic behavioral activities such
as sex, emotion, response to stress and the regulation of body
functions, such as growth, energy use and metabolism. Actions
of hormones show the brain to be very malleable and capable
of responding to environmental signals.


The brain contains receptors for both the thyroid hormone
and the six classes of steroid hormones—estrogens, androgens,
progestins, glucocorticoids, mineralocorticoids and vitamin D. The
receptors are found in selected populations of neurons in the
brain and relevant organs in the body. Thyroid and steroid hormones bind to receptor proteins that in turn bind to the DNA
genetic material and regulate action of genes. This can result in
long-lasting changes in cellular structure and function.
In response to stress and changes in our biological clocks,

such as day-and-night cycles and jet-lag, hormones enter the
blood and travel to the brain and other organs. In the brain,
they alter the production of gene products that participate in
synaptic neurotransmission as well as the structure of brain
cells. As a result, the circuitry of the brain and its capacity for
neurotransmission are changed over a course of hours to days.
In this way, the brain adjusts its performance and control of
behavior in response to a changing environment. Hormones are
important agents of protection and adaptation, but stress and
stress hormones also can alter brain function, including learning. Severe and prolonged stress can cause permanent brain
damage.
Reproduction is a good example of a regular, cyclic process
driven by circulating hormones: The hypothalamus produces
gonadotropin-releasing hormone (GnRH), a peptide that acts on
cells in the pituitary. In both males and females, this causes two
hormones—the follicle-stimulating hormone (FSH) and the
luteinizing hormone (LH)—to be released into the bloodstream.
In males, these hormones are carried to receptors on cells in the
testes where they release the male hormone testosterone into
the bloodstream. In females, FSH and LH act on the ovaries
and cause the release of the female hormones estrogen and progesterone. In turn, the increased levels of testosterone in males
and estrogen in females act back on the hypothalamus and pituitary to decrease the release of FSH and LH. The increased levels also induce changes in cell structure and chemistry that lead
to an increased capacity to engage in sexual behavior.
Scientists have found statistically and biologically significant di∑erences between the brains of men and women that
are similar to sex di∑erences found in experimental animals.
These include di∑erences in the size and shape of brain structures in the hypothalamus and the arrangement of neurons in
the cortex and hippocampus. Some functions can be attributed
to these sex di∑erences, but much more must be learned in
terms of perception, memory and cognitive ability. Although
di∑erences exist, the brains of men and women are more similar than they are di∑erent.

Recently, several teams of researchers have found anatomical di∑erences between the brains of heterosexual and homosexual men. Research suggests that hormones and genes act
early in life to shape the brain in terms of sex-related di∑erences
in structure and function, but scientists still do not have a firm

grip on all the pieces of this puzzle.
Gases Very recently, scientists identified a new class of neurotransmitters that are gases. These molecules—nitric oxide and
carbon monoxide—do not obey the “laws” governing neurotransmitter behavior. Being gases, they cannot be stored in any
structure, certainly not in synaptic storage structures. Instead,
they are made by enzymes as they are needed. They are released
from neurons by di∑usion. And rather than acting at receptor
sites, they simply di∑use into adjacent neurons and act upon
chemical targets, which may be enzymes.
Though only recently characterized, nitric oxide has
already been shown to play important roles. For example, nitric
oxide neurotransmission governs erection in neurons of the
penis. In nerves of the intestine, it governs the relaxation that
contributes to normal movements of digestion. In the brain,
nitric oxide is the major regulator of the intracellular messenger molecule—cyclic GMP. In conditions of excess glutamate
release, as occurs in stroke, neuronal damage following the
stroke may be attributable in part to nitric oxide. Exact functions for carbon monoxide have not yet been shown.

Second messengers
Recently recognized substances that trigger biochemical communication within cells, second messengers may be responsible for long-term changes in the nervous system. They convey
the chemical message of a neurotransmitter (the first messenger) from the cell membrane to the cell’s internal biochemical
machinery. Second messengers take anywhere from a few milliseconds to minutes to transmit a message.
An example of the initial step in the activation of a second
messenger system involves adenosine triphosphate (ATP), the
chemical source of energy in cells. ATP is present throughout
the cell. For example, when norepinephrine binds to its receptors on the surface of the neuron, the activated receptor binds
G-proteins on the inside of the membrane. The activated Gprotein causes the enzyme adenylyl cyclase to convert ATP to

cyclic adenosine monophosphate (cAMP). The second messenger,
cAMP, exerts a variety of influences on the cell, ranging from
changes in the function of ion channels in the membrane to
changes in the expression of genes in the nucleus, rather than
acting as a messenger between one neuron and another. cAMP
is called a second messenger because it acts after the first messenger, the transmitter chemical, has crossed the synaptic space
and attached itself to a receptor.
Second messengers also are thought to play a role in the
manufacture and release of neurotransmitters, intracellular
movements, carbohydrate metabolism in the cerebrum—the
largest part of the brain consisting of two hemispheres—and
the processes of growth and development. Direct e∑ects of
these substances on the genetic material of cells may lead to
long-term alterations of behavior.
7


Brain development

T

hree to four weeks after conception, one of the
two cell layers of the gelatin-like human embryo,
now about one-tenth of an inch long, starts to
thicken and build up along the middle. As this
flat neural plate grows, parallel ridges, similar to
the creases in a paper airplane, rise across its
surface. Within a few days, the ridges fold in toward each other
and fuse to form the hollow neural tube. The top of the tube
thickens into three bulges that form the hindbrain, midbrain

and forebrain. The first signs of the eyes and then the hemispheres of the brain appear later.
How does all this happen? Although many of the mechanisms of human brain development remain secrets, neuroscientists are beginning to uncover some of these complex steps
through studies of the roundworm, fruit fly, frog, zebrafish,
mouse, rat, chicken, cat and monkey.
Many initial steps in brain development are similar across
species, while later steps are different. By studying these similarities and differences, scientists can learn how the human brain
develops and how brain abnormalities, such as mental retardation and other brain disorders, can be prevented or treated.
Neurons are initially produced along the central canal in
the neural tube. These neurons then migrate from their birth-

place to a final destination in the brain. They collect together
to form each of the various brain structures and acquire specific
ways of transmitting nerve messages. Their processes, or axons,
grow long distances to find and connect with appropriate partners, forming elaborate and specific circuits. Finally, sculpting
action eliminates redundant or improper connections, honing
the specificity of the circuits that remain. The result is the creation of a precisely elaborated adult network of 100 billion neurons capable of a body movement, a perception, an emotion or
a thought.
Knowing how the brain is put together is essential for
understanding its ability to reorganize in response to external
influences or to injury. These studies also shed light on brain
functions, such as learning and memory. Brain diseases, such as
schizophrenia and mental retardation, are thought to result
from a failure to construct proper connections during development. Neuroscientists are beginning to discover some general
principles to understand the processes of development, many
of which overlap in time.

Birth of neurons and brain wiring
The embryo has three primary layers that undergo many interactions in order to evolve into organ, bone, muscle, skin or

BRAIN DEVELOPMENT. The human brain and nervous system begin to develop at three weeks’ gestation as the closing neural tube (left).

By four weeks, major regions of the human brain can be recognized in primitive form, including the forebrain, midbrain, hindbrain, and optic vesicle
(from which the eye develops). Irregular ridges, or convolutions, are clearly seen by six months.

Hindbrain

Forebrain
Midbrain

Future
forebrain

Hindbrain

Spinal cord

Optic vesicle

4 WEEKS

Future
spinal
cord

Forebrain

3 WEEKS

8

7 WEEKS

3 MONTHS

6 MONTHS

9 MONTHS


neural tissue. The skin and neural tissue arise from a single
layer, known as the ectoderm, in response to signals provided
by an adjacent layer, known as the mesoderm.
A number of molecules interact to determine whether the
ectoderm becomes neural tissue or develops in another way to
become skin. Studies of spinal cord development in frogs show
that one major mechanism depends on specific molecules that
inhibit the activity of various proteins. If nothing interrupts the
activity of such proteins, the tissue becomes skin. If other molecules, which are secreted from mesodermal tissue, block protein signaling, then the tissue becomes neural.
Once the ectodermal tissue has acquired its neural fate,
another series of signaling interactions determine the type of
neural cell to which it gives rise. The mature nervous system
contains a vast array of cell types, which can be divided into two
main categories: the neurons, primarily responsible for signaling, and supporting cells called glial cells.
Researchers are finding that the destiny of neural tissue
depends on a number of factors, including position, that define
the environmental signals to which the cells are exposed. For
example, a key factor in spinal cord development is a secreted
protein called sonic hedgehog that is similar to a signaling protein found in flies. The protein, initially secreted from mesodermal tissue lying beneath the developing spinal cord, marks
young neural cells that are directly adjacent to become a specialized class of glial cells. Cells further away are exposed to
lower concentrations of sonic hedgehog protein, and they

become the motor neurons that control muscles. An even lower
concentration promotes the formation of interneurons that
relay messages to other neurons, not muscles.
A combination of signals also determines the type of chemical messages, or neurotransmitters, that a neuron will use to
communicate with other cells. For some, such as motor neurons, the choice is invariant, but for others it is a matter of
choice. Scientists found that when certain neurons are maintained in a dish without any other cell type, they produce the
neurotransmitter norepinephrine. In contrast, if the same neurons are maintained with other cells, such as cardiac or heart
tissue cells, they produce the neurotransmitter acetylcholine.
Since all neurons have genes containing the information for the
production of these molecules, it is the turning on of a particular set of genes that begins the production of specific neurotransmitters. Many researchers believe that the signal to engage
the gene and, therefore, the final determination of the chemical messengers that a neuron produces, is influenced by factors
coming from the targets themselves.
As neurons are produced, they move from the neural tube’s
ventricular zone, or inner surface, to near the border of the marginal zone, or the outer surface. After neurons stop dividing,
they form an intermediate zone where they gradually accumulate as the brain develops.
The migration of neurons occurs in most structures of the
brain, but is particularly prominent in the formation of a large
cerebral cortex in primates, including humans. In this structure,
NEURON MIGRATION. A crosssectional view of the occipital

Outer surface

lobe (which processes vision) of
a three-month-old monkey fetus

Fetal
monkey
brain

brain (center) shows immature

neurons migrating along glial
Migrating
neuron

fibers. These neurons make
transient connections with other
neurons before reaching their
destination. A single migrating
neuron, shown about 2,500
times its actual size (right), uses

Migrating
zone

a glial fiber as a guiding
sca≈old. To move, it needs adhesion molecules, which recogGlial
fiber

nize the pathway, and contractile proteins to propel it along.

Inner surface

9


neurons slither from the place of origin near the ventricular surface along nonneuronal fibers that form a trail to their proper
destination. Proper neuron migration requires multiple mechanisms, including the recognition of the proper path and the
ability to move long distances. One such mechanism for long
distance migration is the movement of neurons along elongated
fibers that form transient scaffolding in the fetal brain. Many

external forces, such as alcohol, cocaine or radiation, prevent
proper neuronal migration and result in misplacement of cells,
which may lead to mental retardation and epilepsy. Furthermore, mutations in genes that regulate migration have recently
been shown to cause some rare genetic forms of retardation and
epilepsy in humans.
Once the neurons reach their final location, they must make
the proper connections for a particular function, such as vision
or hearing, to occur. They do this through their axons. These
stalk-like appendages can stretch out a thousand times longer
than the cell body from which they arise. The journey of most
axons ends when they meet the branching areas, called dendrites, on other neurons. These target neurons can be located
at a considerable distance, sometimes at opposite sides of the
brain. In the case of a motor neuron, the axon may travel from
the spinal cord all the way down to a foot muscle. The linkup
sites, called synapses, are where messages are transferred from
one neuron in a circuit to the next.
Axon growth is spearheaded by growth cones. These enlargements of the axon’s tip actively explore the environment as they
seek out their precise destinations. Researchers have discovered
that many special molecules help guide growth cones. Some
molecules lie on the cells that growth cones contact, while others are released from sources found near the growth cone. The
growth cones, in turn, bear molecules that serve as receptors for
the environmental cues. The binding of particular signals with
its receptors tells the growth cone whether to move forward,
stop, recoil or change direction.
Recently researchers have identified some of the molecules
that serve as cues and receptors. These molecules include proteins with names such as cadherin, netrin, semaphorin, ephrin,
neuropilin and plexin. In most cases, these are families of
related molecules; for example there are at least 15 semapohorins and at least 10 ephrins. Perhaps the most remarkable
result is that most of these are common to worms, insects and
mammals, including humans. Each family is smaller in flies

or worms than in mice or people, but their functions are quite
similar. It has therefore been possible to use the simpler animals to gain knowledge that can be directly applied to
humans. For example, the first netrin was discovered in a
worm and shown to guide neurons around the worm’s “nerve
ring.” Later, vertebrate netrins were found to guide axons
around the mammalian spinal cord. Worm receptors for
netrins were then found and proved invaluable in finding the
10

corresponding, and again related, human receptors.
Once axons reach their targets, they form synapses, which
permit electric signals in the axon to jump to the next cell, where
they can either provoke or prevent the generation of a new signal. The regulation of this transmission at synapses, and the integration of inputs from the thousands of synapses each neuron
receives, are responsible for the astounding informationprocessing capabilities of the brain. For processing to occur properly, the connections must be highly specific. Some specificity
arises from the mechanisms that guide each axon to its proper
target area. Additional molecules mediate “target recognition”
whereby the axon chooses the proper neuron, and often the
proper part of the target, once it arrives at its destination. Few of
these molecules have been identified. There has been more success, however, in identifying the ways in which the synapse forms
once the contact has been made. The tiny portion of the axon
that contacts the dendrite becomes specialized for the release of
neurotransmitters, and the tiny portion of the dendrite that
receives the contact becomes specialized to receive and respond
to the signal. Special molecules pass between the sending and
receiving cell to ensure that the contact is formed properly.

Paring back
Following the period of growth, the network is pared back to
create a more sturdy system. Only about one-half of the neurons generated during development survive to function in the
adult. Entire populations of neurons are removed through

internal suicide programs initiated in the cells. The programs
are activated if a neuron loses its battle with other neurons to
receive life-sustaining nutrients called trophic factors. These
factors are produced in limited quantities by target tissues. Each
type of trophic factor supports the survival of a distinct group
of neurons. For example, nerve growth factor is important for
sensory neuron survival. It has recently become clear that the
internal suicide program is maintained into adulthood, and
constantly held in check. Based on this idea, researchers have
found that injuries and some neurodegenerative diseases kill
neurons not directly by the damage they inflict, but rather by
activating the death program. This discovery, and its implication that death need not inevitably follow insult, have led to
new avenues for therapy.
Brain cells also form too many connections at first. For
example, in primates, the projection from the two eyes to the
brain initially overlaps, and then sorts out to separate territories devoted only to one or the other eye. Furthermore, in the
young primate cerebral cortex, the connections between neurons are greater in number and twice as dense as an adult primate. Communication between neurons with chemical and
electrical signals is necessary to weed out the connections. The
connections that are active and generating electrical currents
survive while those with little or no activity are lost.


SPINAL CORD AND NERVES. The
mature central nervous system

CENTRAL NERVOUS SYSTEM
Brain and spinal cord

(CNS) consists of the brain and
spinal cord. The brain sends

nerve signals to specific parts of
Cervical region

PERIPHERAL NERVOUS SYSTEM
Nerves extending from spinal cord

the body through peripheral
nerves, known as the peripheral
nervous system (PNS). Peripheral
nerves in the cervical region

Thoracic region

serve the neck and arms; those in
the thoracic region serve the
trunk; those in the lumbar region
serve the legs; and those in the

Peripheral nerves

Lumbar region

sacral region serve the bowels
and bladder. The PNS consists of
the somatic nervous system that

Sacral region

connects voluntary skeletal muscles with cells specialized to respond to sensations, such as
touch and pain. The autonomic

nervous system is made of neurons connecting the CNS with
internal organs. It is divided into
the sympathetic nervous system,
which mobilizes energy and

Vertebrae

Spinal cord

resources during times of stress
and arousal, and the parasympathetic nervous system, which
conserves energy and resources
during relaxed states.

Critical periods
The brain’s refining and building of the network in mammals,
including humans, continues after birth. An organism’s interactions with its surroundings fine-tune connections.
Changes occur during critical periods. These are windows of
time during development when the nervous system must obtain
certain critical experiences, such as sensory, movement or emotional input, to develop properly. Following a critical period, connections become diminished in number and less subject to
change, but the ones that remain are stronger, more reliable and
more precise. Injury, sensory or social deprivation occurring at a
certain stage of postnatal life may affect one aspect of development, while the same injury at a different period may affect
another aspect. In one example, a monkey is raised from birth
up to six months of age with one eyelid closed. As a result of

diminished use, the animal permanently loses useful vision in
that eye. This gives cellular meaning to the saying “use it or lose
it.” Loss of vision is caused by the actual loss of functional connections between that eye and neurons in the visual cortex. This
finding has led to earlier and better treatment of the eye disorders congenital cataracts and “crossed-eyes” in children.

Research also shows that enriched environments can bolster
brain development during postnatal life. For example, studies
show that animals brought up in toy-filled surroundings have more
branches on their neurons and more connections than isolated animals. In one recent study, scientists found enriched environments
resulted in more neurons in a brain area involved in memory.
Scientists hope that new insights on development will lead
to treatments for those with learning disabilities, brain damage
and even neurodegenerative disorders or aging.
11


Sensation and perception

V

ision. This wonderful sense allows us to
image the world around us from the genius
of Michelangelo’s Sistine Chapel ceiling to
mist-filled vistas of a mountain range. Vision
is one of the most delicate and complicated
of all the senses.
It also is the most studied. About one-fourth of the brain
is involved in visual processing, more than for all other senses.
More is known about vision than any other vertebrate sensory
system, with most of the information derived from studies of
monkeys and cats.
Vision begins with the cornea, which does about threequarters of the focusing, and then the lens, which varies the
focus. Both help produce a clear image of the visual world on
the retina, the sheet of photoreceptors, which process vision,
and neurons lining the back of the eye.

As in a camera, the image on the retina is reversed: objects
to the right of center project images to the left part of the retina
and vice versa. Objects above the center project to the lower
part and vice versa. The shape of the lens is altered by the muscles of the iris so near or far objects can be brought into focus
on the retina.
Visual receptors, about 125 million in each eye, are neurons
specialized to turn light into electrical signals. They occur in
two forms. Rods are most sensitive to dim light and do not convey the sense of color. Cones work in bright light and are
responsible for acute detail, black and white and color vision.
The human eye contains three types of cones that are sensitive
to red, green and blue but in combination convey information
about all visible colors.
Primates, including humans, have well-developed vision
using two eyes. Visual signals pass from each eye along the million or so fibers of the optic nerve to the optic chiasma where
some nerve fibers cross over, so both sides of the brain receive
signals from both eyes. Consequently, the left halves of both
retinae project to the left visual cortex and the right halves project to the right visual cortex.
The e∑ect is that the left half of the scene you are watching registers in your right hemisphere. Conversely, the right half
12

of the scene you are watching registers in your left hemisphere.
A similar arrangement applies to movement and touch: each
half of the cerebrum is responsible for the opposite half of the
body.
Scientists know much about the way cells code visual information in the retina, lateral geniculate nucleus—an intermediate point between the retina and visual cortex—and visual cortex. These studies give us the best knowledge so far about how
the brain analyzes and processes information.
The retina contains three stages of neurons. The first, the
layer of rods and cones, sends its signals to the middle layer,
which relays signals to the third layer. Nerve fibers from the
third layer assemble to form the optic nerve. Each cell in the

middle or third layer receives input from many cells in the previous layer. Any cell in the third layer thus receives signals—
via the middle layer—from a cluster of many thousands of rods
and cones that cover about one-square millimeter (the size of
a thumb tack hole). This region is called the receptive field of
the third-layer cell.
About 50 years ago, scientists discovered that the receptive
field of such a cell is activated when light hits a tiny region in
its receptive field center and is inhibited when light hits the part
of the receptive field surrounding the center. If light covers the
entire receptive field, the cell reacts only weakly and perhaps
not at all.
Thus, the visual process begins with a comparison of the
amount of light striking any small region of the retina and the
amount of light around it. Located in the occipital lobe, the primary visual cortex—two millimeters thick (twice that of a
dime) and densely packed with cells in many layers—receives
messages from the lateral geniculate. In the middle layer, which
receives input from the lateral geniculate, scientists found patterns of responsiveness similar to those observed in the retina
and lateral geniculate cells. Cells above and below this layer
responded di∑erently. They preferred stimuli in the shape of
bars or edges. Further studies showed that di∑erent cells preferred edges at particular angles, edges that moved or edges
moving in a particular direction.
Although the process is not yet completely understood,


Third cell layer

Middle cell layer

Rods and Cones

Pupil

Rods

Cones

Lens
Optic nerve

Retina

Visual cortex

Cornea

Iris

Lateral geniculate nucleus

Optic chiasm

Optic nerve

Right visual field

Left visual field
Modified from Jane Hurd

VISION. The cornea and lens help produce a clear image of the visual world on the retina, the sheet of photoreceptors and neurons lining the back
of the eye. As in a camera, the image on the retina is reversed: objects to the right of center project images to the left part of the retina and vice

versa. The eye’s 125 million visual receptors—composed of rods and cones—turn light into electrical signals. Rods are most sensitive to dim light
and do not convey the sense of color; cones work in bright light and are responsible for acute detail, black and white and color vision. The human
eye contains three types of cones that are sensitive to red, green and blue but, in combination, convey information about all visible colors. Rods and
cones connect with a middle cell layer and third cell layer (see inset, above). Light passes through these two layers before reaching the rods and
cones. The two layers then receive signals from rods and cones before transmitting the signals onto the optic nerve, optic chiasm, lateral geniculate
nucleus and, finally, the visual cortex.

13


External ear

Middle ear

Inner ear
Auditory area

BONES OF THE MIDDLE EAR
Malleus

Incus

Stapes

Oval
window

To brain

HEARING. From the chirping of

Auditory nerve

crickets to the roar of a rocket
engine, almost all of the thou-

Cochlea

sands of single tones processed
by the human ear are heard by a
Tympanic
membrane

mechanism known as air conduction. In this process, sound

Soundwaves

Displacement of hair bundles

External
auditory
canal

waves are first funneled
through the external ear—the
pinna and the external auditory
canal—to the middle ear—the

Hair cell
of cochlea

tympanic membrane (eardrum)
Pinna

that vibrates at di≈erent

Nucleus

speeds. The malleus (hammer),

Transmitters
released

which is attached to the tym-

Released
chemicals
excite nerve
and send
impulses to
brain

panic membrane, transmits the
vibrations to the incus (anvil).
The vibrations are then passed
onto the stapes (stirrup) and
oval window that, in turn, pass
them onto the inner ear. In the
inner ear, the fluid-filled spiral
passage of the cochlea contains
cells with microscopic, hairlike

projections that respond to the
vibrations produced by sound.
The hair cells, in turn, excite the
28,000 fibers of the auditory
nerve that end in the medulla in
the brain. Auditory information
flows via the thalamus to the
temporal gyrus, the part of the
cerebral cortex involved in
receiving and perceiving sound.

14

recent findings suggest that visual signals are fed into at least three separate processing systems.
One system appears to process information about shape; a second, color; and a third, movement,
location and spatial organization. These findings of separate processing systems come from monkey anatomical and physiological data. They are verified by human psychological studies showing
that the perception of movement, depth, perspective, the relative size of objects, the relative movement of objects and shading and gradations in texture all depend primarily on contrasts in light
intensity rather than in color.
Why movement and depth perception should be carried by only one processing system may
be explained by a school of thought called Gestalt psychology. Perception requires various elements to be organized so that related ones are grouped together. This stems from the brain’s ability to group the parts of an image together and also to separate images from one another and from
their individual backgrounds.
How do all these systems produce the solid images you see? By extracting biologically relevant information at each stage and associating firing patterns with past experience.
Vision studies also have led to better treatment for visual disorders. Information from research
in cats and monkeys has improved the therapy for strabismus, or squint, a term for “cross-eye” or
wall-eye. Children with strabismus initially have good vision in each eye. But because they cannot fuse the images in the two eyes, they tend to favor using one eye and often lose useful vision
in the other eye.
Vision can be restored but only during infancy or early childhood. Beyond the age of six or
so, the blindness becomes permanent. But until a few decades ago, ophthalmologists waited until

children reached the age of four before operating to align the
eyes, or prescribe exercises or an eye patch. Now strabismus is
corrected very early in life—before age four—when normal
vision can still be restored.

Taste and smell

Although di∑erent, the two sensory experiences of taste and
smell are intimately entwined. They are separate senses with
their own receptor organs. However, these two senses act
together to allow us to distinguish thousands of di∑erent
Hearing
flavors. Alone, taste is a relatively focused sense concerned with
Often considered the most important sense for humans, heardistinguishing among sweet, salty, sour and bitter. The interacing allows us to communicate with each other by receiving
tion between taste and smell explains why loss of the sense of
sounds and interpreting speech. It also gives us information
smell apparently causes a serious reduction in the overall taste
vital to survival. For example, the sound of an oncoming train
experience, which we call flavor.
tells us to stay clear of the railroad track.
Tastes are detected by taste buds, special structures of which
every human has some 5,000. Taste buds are embedded within
Like the visual system, our hearing system distinguishes sevpapillae, or protuberances, located mainly on the tongue, with
eral qualities in the signal it detects. However, our hearing system
others found in the back of the mouth and on the palate. Taste
does not blend di∑erent sounds, as the visual system does when
substances stimulate hairs protwo di∑erent wavelengths of
jecting from the sensory cells.
light are mixed to produce
Taste and smell are two separate senses with Each taste bud consists of 50 to

color. We can follow the sep100 sensory cells that respond
arate melodic lines of several
their own sets of receptor organs, but they act to salts, acidity, sweet subinstruments as we listen to an
stances and bitter compounds.
orchestra or rock band.
together to distinguish an enormous number of Some researchers add a fifth
From the chirping of
category named umami, for the
crickets to the roar of a rocket
di≈erent flavors.
taste of monosodium glutaengine, most of the sounds
mate and related substances.
processed by the ear are heard
Taste signals in the sensory cells are transferred by synapses
by a mechanism known as air conduction. In this process, sound
waves are first funneled through the externally visible part of the
to the ends of nerve fibers, which send impulses along cranial
ear, the pinna (or external ear) and the external auditory canal to
nerves to taste centers in the brain. From here, the impulses are
the tympanic membrane (eardrum) that vibrates at di∑erent
relayed to other brain stem centers responsible for the basic
speeds. The malleus (hammer), which is attached to the tymresponses of acceptance or rejection of the tastes, and to the
panic membrane, transmits the vibrations to the incus (anvil).
thalamus and on to the cerebral cortex for conscious perception
This structure passes them onto the stapes (stirrup) which delivof taste.
ers them, through the oval window, to the inner ear.
Specialized smell receptor cells are located in a small patch
The fluid-filled spiral passages of each cochlea contain
of mucus membrane lining the roof of the nose. Axons of these
16,000 hair cells whose microscopic, hairlike projections

sensory cells pass through perforations in the overlying bone
respond to the vibrations produced by sound. The hair cells, in
and enter two elongated olfactory bulbs lying on top of the bone.
The portion of the sensory cell that is exposed to odors posturn, excite the 28,000 fibers of the auditory nerve that termisesses hair-like cilia. These cilia contain the receptor sites that
nate in the medulla of the brain. Auditory information flows
are stimulated by odors carried by airborne molecules. The odor
via the thalamus to the temporal gyrus, the part of the cerebral
cortex involved in receiving and perceiving sound.
molecules dissolve in the mucus lining in order to stimulate
The brain’s analysis of auditory information follows a patreceptor molecules in the cilia to start the smell response. An
tern similar to that of the visual system. Adjacent neurons
odor molecule acts on many receptors to di∑erent degrees. Simrespond to tones of similar frequency. Some neurons respond
ilarly, a receptor interacts with many di∑erent odor molecules
to only a small range of frequencies, others react to a wide
to di∑erent degrees.
range; some react only to the beginning of a sound, others only
Axons of the cells pass through perforations in the overlyrespond to the end.
ing bone and enter two elongated olfactory bulbs lying on top
Speech sounds, however, may be processed di∑erently than
of the bone. The pattern of activity set up in the receptor cells
is projected to the olfactory bulb, where it forms a spatial image
others. Our auditory system processes all the signals that it
of the odor. Impulses created by this stimulation pass to smell
receives in the same way until they reach the primary auditory
centers, to give rise to conscious perceptions of odor in the
cortex in the temporal lobe of the brain. When speech sound
frontal lobe and emotional responses in the limbic system of
is perceived, the neural signal is funneled to the left hemisphere
the brain.
for processing in language centers.

15


SMELL AND TASTE. Specialized
receptors for smell are located

Nerve fibers to brain

in a patch of mucous membrane
Receptor cells

lining the roof of the nose. Each

Olfactory tract

cell has several fine hairlike
cilia containing receptor proteins, which are stimulated by
odor molecules in the air, and a

Olfactory
bulb

long fiber (axon), which passes
through perforations in the
overlying bone to enter the
olfactory bulb. Stimulated cells
Airborne odors

give rise to impulses in the
Cilia

fibers, which set up patterns in
the olfactory bulb that are
relayed to the brain’s frontal

Food
chemicals

Taste bud pore

lobe to give rise to smell perception, and to the limbic system to elicit emotional
responses. Tastes are detected
by special structures, taste
Tongue

buds, of which every human has
some 10,000. Taste buds are
Synapse

embedded within papillae (protuberances) mainly on the

Taste (gustatory) nerve to brain

tongue, with a few located in
the back of the mouth and on
the palate. Each taste bud consists of about 100 receptors that
respond to the four types of
stimuli—sweet, salty, sour and
bitter—from which all tastes are
formed. A substance is tasted

when chemicals in foods dissolve in saliva, enter the pores
on the tongue and come in contact with taste buds. Here they
stimulate hairs projecting from
the receptor cells and cause signals to be sent from the cells,
via synapses, to cranial nerves
and taste centers in the brain.

16

Touch and pain
Touch is the sense by which we determine the characteristics of objects: size, shape and texture.
We do this through touch receptors in the skin. In hairy skin areas, some receptors consist of webs
of sensory nerve cell endings wrapped around the hair bulbs. They are remarkably sensitive, being
triggered when the hairs are moved. Other receptors are more common in non-hairy areas, such
as lips and fingertips, and consist of nerve cell endings that may be free or surrounded by bulblike structures.
Signals from touch receptors pass via sensory nerves to the spinal cord, then to the thalamus
and sensory cortex. The transmission of this information is highly topographic, meaning that the
body is represented in an orderly fashion at di∑erent levels of the nervous system. Larger areas of
the cortex are devoted to sensations from the hands and lips; much smaller cortical regions represent less sensitive parts of the body.
Di∑erent parts of the body vary in their sensitivity to touch discrimination and painful stimuli according to the number and distribution of receptors. The cornea is several hundred times
more sensitive to painful stimuli than are the soles of the feet. The fingertips are good at touch
discrimination but the chest and back are less sensitive.
Until recently, pain was thought to be a simple message by which neurons sent electrical
impulses from the site of injury directly to the brain.
Recent studies show that the process is more complicated. Nerve impulses from sites of injury
that persist for hours, days or longer lead to changes in the nervous system that result in an
amplification and increased duration of the pain. These changes involve dozens of chemical messengers and receptors.


At the point of injury, nociceptors, special receptors, respond

to tissue-damaging stimuli. Injury results in the release of
numerous chemicals at the site of damage and inflammation.
One such chemical, prostaglandin, enhances the sensitivity of
receptors to tissue damage and ultimately can result in more
intense pain sensations. It also contributes to the clinical condition in which innocuous stimuli can produce pain (such as in
sunburned skin) because the threshold of the nociceptor is
significantly reduced.
Pain messages are transmitted to the spinal cord via small
myelinated fibers and C fibers—very small unmyelinated fibers.
Myelin is a covering around nerve fibers that helps them send
their messages more rapidly.
In the ascending system, the impulses are relayed from the
spinal cord to several brain structures, including the thalamus
and cerebral cortex, which are involved in the process by which
“pain” messages become conscious experience.

Pain messages can also be suppressed by a system of neurons that originate within the gray matter in the brainstem of
the midbrain. This descending system sends messages to the dorsal horn of the spinal cord where it suppresses the transmission
of pain signals to the higher brain centers. Some of these
descending systems use naturally occurring chemicals similar to
opioids. The three major families of opioids—enkephalins,
endorphins and dynorphins—identified in the brain originate
from three precursor proteins coded by three di∑erent genes.
They act at multiple opioid receptors in the brain and spinal
cord. This knowledge has led to new treatments for pain: Opiatelike drugs injected into the space above the spinal cord provide
long-lasting pain relief.
Scientists are now using modern tools for imaging brain
structures in humans to determine the role of the higher centers of the brain in pain experience and how signals in these
structures change with long-lasting pain.

PAIN. Messages about tissue
damage are picked up by recep-

Message is received in the thalamus and cerebral cortex

tors and transmitted to the
spinal cord via small, myelinated fibers and very small
unmyelinated fibers. From the

Tissue-damaging stimulus
activates nociceptors

spinal cord, the impulses are
carried to the brainstem, thalamus and cerebral cortex and
ultimately perceived as pain.
These messages can be supDescending pathway

pressed by a system of neurons
that originates in the gray
matter of the midbrain. This
descending pathway sends mes-

Message carried
to spinal cord

sages to the spinal cord where it
suppresses the transmission of
tissue damage signals to the
higher brain centers. Some of
From brain

To brain

these descending pathways use

Nociceptors
Dorsal horn

naturally occurring, opiate-like
chemicals called endorphins.

Muscle fiber

17


Learning and memory

T

he conscious memory of a patient known as
H.M. is limited almost entirely to events that
occurred years before his surgery, which
removed part of the medial temporal lobe of his
brain to relieve epilepsy. H.M. can remember
recent events for only a few minutes. Talk with
him awhile and then leave the room. When you return, he has
no recollection of ever having seen you before.
The medial temporal lobe, which includes the hippocampus and adjacent brain areas, seems to play a role in converting
memory from a short-term to a long-term, permanent form.

The fact that H.M. retains memories for events that are remote
to his surgery is evidence that the medial temporal region is not
the site of permanent storage but that it plays a role in the formation of new memories. Other patients like H.M. have also
been described.
Additional evidence comes from patients undergoing electroconvulsive therapy (ECT) for depression. ECT is thought to
temporarily disrupt the function of the hippocampus and
related structures. These patients typically su∑er di≈culty with
new learning and have amnesia for events that occurred during
the several years before treatment. Memory of earlier events is
unimpaired. As time passes after treatment, much of the lost
part of memory becomes available once again.
The hippocampus and the medial temporal region are connected with widespread areas of the cerebral cortex, especially
the vast regions responsible for thinking and language. Whereas
the medial temporal region is important for forming and organizing memory, cortical areas are important for the long-term
storage of knowledge about facts and events and for how these
are used in everyday situations.
Working memory, a type of transient memory that enables
us to retain what someone has said just long enough to reply,
depends in part on the prefrontal cortex. Researchers discovered that certain neurons in this area are influenced by neurons
releasing dopamine and other neurons releasing glutamate.
While much is unknown about learning and memory, scientists can recognize certain pieces of the process. For example, the
brain appears to process di∑erent kinds of information in sepa18

rate ways and then store it di∑erently. Procedural knowledge, the
knowledge of how to do something, is expressed in skilled behavior and learned habits. Declarative knowledge provides an explicit,
consciously accessible record of individual previous experiences
and a sense of familiarity about those experiences. Declarative
knowledge requires processing in the medial temporal region and
parts of the thalamus, while procedural knowledge requires processing by the basal ganglia. Other kinds of memory depend on
the amygdala (emotional aspects of memory) and the cerebellum

(motor learning where precise timing is involved).
An important factor that influences what is stored and how
strongly it is stored is whether the action is followed by rewarding or punishing consequences. This is an important principle
in determining what behaviors an organism will learn and
remember. The amygdala appears to play an important role in
these memory events.
How exactly does memory occur? After years of study, there
is much support for the idea that memory involves a persistent
change in the relationship between neurons. In animal studies,
scientists found that this occurs through biochemical events in
the short term that a∑ect the strength of the relevant synapses.
The stability of long-term memory is conferred by structural
modifications within neurons that change the strength and
number of synapses. For example, researchers can correlate
specific chemical and structural changes in the relevant cells
with several simple forms of behavioral change exhibited by the
sea slug Aplysia.
Another important model for the study of memory is the
phenomenon of long-term potentiation (LTP), a long-lasting
increase in the strength of a synaptic response following stimulation. LTP occurs prominently in the hippocampus, as well
as in other brain areas. Studies of rats suggest LTP occurs by
changes in synaptic strength at contacts involving NMDA
receptors. It is now possible to study LTP and learning in
genetically modified mice that have abnormalities of specific
genes. Abnormal gene expression can be limited to particular
brain areas and time periods, such as during learning.
Scientists believe that no single brain center stores memory. It most likely is stored in the same, distributed collection


LEARNING AND MEMORY,

BASAL GANGLIA
Cerebral cortex

SPEECH AND LANGUAGE.
Structures believed to be important for various kinds of learning
and memory include the cere-

Caudate
nucleus

bral cortex, amygdala, hip-

Putamen

pocampus, cerebellum and

Globus
pallidus
Amygdaloid
nucleus

basal ganglia. Areas of the left
hemisphere (inset) are known to
be active in speech and language. The form and meaning of
an utterance is believed to arise
in Wernicke’s area and then

AREAS OF SPEECH
AND LANGUAGE

Broca’s area, which is related to
vocalization. Wernicke’s area is

Amygdala

Broca’s area
Wernicke’s area

Hippocampus

Angular
gyrus

also important for language
comprehension.

Cerebellum

of cortical processing systems involved in the perception, processing and analysis of the material being learned. In short,
each part of the brain most likely contributes di∑erently to permanent memory storage.
One of the most prominent intellectual activities dependent on memory is language. While the neural basis of language is not fully understood, scientists have learned much
about this feature of the brain from studies of patients who have
lost speech and language abilities due to stroke, and from behavioral and functional neuroimaging studies of normal people.
A prominent and influential model, based on studies of
these patients, proposes that the underlying structure of speech
comprehension arises in Wernicke’s area, a portion of the left
hemisphere of the brain. This temporal lobe region is connected
with Broca’s area in the frontal lobe where a program for vocal
expression is created. This program is then transmitted to a
nearby area of the motor cortex that activates the mouth,

tongue and larynx.
This same model proposes that, when we read a word, the
information is transmitted from the primary visual cortex to the
angular gyrus where the message is somehow matched with the
sounds of the words when spoken. The auditory form of the

word is then processed for comprehension in Wernicke’s area
as if the word had been heard. Writing in response to an oral
instruction requires information to be passed along the same
pathways in the opposite direction—from the auditory cortex
to Wernicke’s area to the angular gyrus. This model accounts
for much of the data from patients, and is the most widely used
model for clinical diagnosis and prognosis. However, some
refinements to this model may be necessary due to both recent
studies with patients and functional neuroimaging studies in
normal people.
For example, using an imaging technique called positron
emission tomography (PET), scientists have demonstrated that
some reading tasks performed by normal people activated neither Wernicke’s area nor the angular gyrus. These results suggest that there is a direct reading route that does not involve
speech sound recoding of the visual stimulus before the processing of either meaning or speaking. Other studies with
patients also have indicated that it is likely that familiar words
need not be recoded into sound before they can be understood.
Although the understanding of how language is implemented in the brain is far from complete, there are now several
techniques that may be used to gain important insights.
19


Movement

F

rom the stands, we marvel at the perfectly placed
serves of professional tennis players and lightningfast double plays executed by big league infielders.
But in fact, every one of us in our daily lives performs highly skilled movements, such as walking
upright, speaking and writing, that are no less
remarkable. A finely tuned and highly complex central nervous
system controls the action of hundreds of muscles in accomplishing these everyday marvels.
In order to understand how the nervous system performs
this trick, we have to start with muscles. Most muscles attach
to points on the skeleton that cross one or more joints. Activation of a given muscle, the agonist, can open or close the
joints that it spans or act to sti∑en them, depending on the
forces acting on those joints from the environment or other
muscles that oppose the agonist, the antagonists. Relatively few
muscles act on soft tissue. Examples include the muscles that
move the eyes and tongue, and the muscles that control facial
expression.
A muscle is made up of thousands of individual muscle
fibers, each of which is controlled by one alpha motor neuron in
either the brain or spinal cord. On the other hand, a single
alpha neuron can control hundreds of muscle fibers, forming a
motor unit. These motor neurons are the critical link between
the brain and muscles. When these neurons die, a person is no
longer able to move.
The simplest movements are reflexes—fixed muscle
responses to particular stimuli. Studies show sensory stretch
receptors—called muscle spindles, which include small, specialized muscle fibers and are located in most muscles—send information about muscles directly to alpha motor neurons.
Sudden muscle stretch (such as when a doctor taps a muscle tendon to test your reflexes) sends a barrage of impulses into
the spinal cord along the muscle spindle sensory fibers. This,
in turn, activates motor neurons in the stretched muscle, causing a contraction which is called the stretch reflex. The same
sensory stimulus causes inactivation, or inhibition, in the motor

neurons of the antagonist muscles through connecting neurons,
called inhibitory neurons, within the spinal cord.

20

The sensitivity of the muscle spindle organs is controlled
by the brain through a separate set of gamma motor neurons that
control the specialized spindle muscle fibers and allow the brain
to fine-tune the system for di∑erent movement tasks. Other
muscle sense organs signal muscle force that a∑ects motor neurons through separate sets of spinal neurons. We now know that
this complex system responds di∑erently for tasks that require
precise control of position (holding a full teacup), as opposed
to those that require rapid, strong movement (throwing a ball).
You can experience such changes in motor strategy when you
compare walking down an illuminated staircase with the same
task done in the dark.
Another useful reflex is the flexion withdrawal that occurs
if your bare foot encounters a sharp object. Your leg is immediately lifted from the source of potential injury (flexion) but
the opposite leg responds with increased extension in order to
maintain your balance. The latter event is called the crossed
extension reflex. These responses occur very rapidly and without
your attention because they are built into systems of neurons
located within the spinal cord itself.
It seems likely that the same systems of spinal neurons also
participate in controlling the alternating action of the legs during normal walking. In fact, the basic patterns of muscle activation that produce coordinated walking can be generated in
four-footed animals within the spinal cord itself. It seems likely
that these spinal mechanisms, which evolved in primitive vertebrates, are probably still present in the human spinal cord.
The most complex movements that we perform, including
voluntary ones that require conscious planning, involve control
of the spinal mechanisms by the brain. Scientists are only

beginning to understand the complex interactions that take
place between di∑erent brain regions during voluntary movements, mostly through careful experiments on animals. One
important area is the motor cortex, which exerts powerful control of the spinal cord neurons and has direct control of some
motor neurons in monkeys and humans. Some neurons in the
motor cortex appear to specify the coordinated action of many
muscles, so as to produce organized movement of the limb to
a particular place in space.


MOVEMENT. The stretch reflex
(above) occurs when a doctor taps

Sensory neuron

a muscle tendon to test your
reflexes. This sends a barrage of
impulses into the spinal cord

Alpha motor neuron
Extensor muscles activated

along muscle spindle sensory
Muscle
spindle

Inhibitory neuron

fibers and activates motor neurons to the stretched muscle to
cause contraction (stretch reflex).
The same sensory stimulus

Flexor muscles inhibited

causes inactivation, or inhibition,
of the motor neurons to the antag-

Stimulus

onist muscles through connection
Response

neurons, called inhibitory neuEfferent nerves
Afferent nerves

rons, within the spinal cord.
A≈erent nerves carry messages
from sense organs to the spinal
cord; e≈erent nerves carry motor

Inhibitory neurons

commands from the spinal cord to
Excitatory neurons

muscles. Flexion withdrawal

Sensory neuron

(below) can occur when your bare
foot encounters a sharp object.

Extensor
muscles
inhibited

Motor neurons

Your leg is immediately lifted
(flexion) from the source of poten-

-

Extensor muscles activated
Motor
neurons

tial injury, but the opposite leg
responds with increased extension in order to maintain your bal-

Flexor
muscles
activated

ance. The latter event is called the
Flexor
muscles
inhibited

crossed extension reflex. These
responses occur very rapidly and
without your attention because

Right leg extends to
balance body

they are built into systems of neurons located within the spinal
cord itself.

Stimulus

In addition to the motor cortex, movement control also
involves the interaction of many other brain regions, including
the basal ganglia and thalamus, the cerebellum and a large
number of neuron groups located within the midbrain and
brainstem—regions that connect cerebral hemispheres with the
spinal cord.
Scientists know that the basal ganglia and thalamus have
widespread connections with sensory and motor areas of the
cerebral cortex. Loss of regulation of the basal ganglia by
dopamine depletion can cause serious movement disorders,
such as Parkinson’s disease. Loss of dopamine neurons in the
substantia nigra on the midbrain, which connects with the basal
ganglia, is a major factor in Parkinson’s.

The cerebellum is critically involved in the control of all
skilled movements. Loss of cerebellar function leads to poor
coordination of muscle control and disorders of balance. The
cerebellum receives direct and powerful sensory information
from the muscle receptors, and the sense organs of the inner
ear, which signal head position and movement, as well as signals from the cerebral cortex. It apparently acts to integrate all
this information to ensure smooth coordination of muscle

action, enabling us to perform skilled movements more or less
automatically. There is evidence that, as we learn to walk, speak
or play a musical instrument, the necessary detailed control
information is stored within the cerebellum where it can be
called upon by commands from the cerebral cortex.
21


Sleep

S

leep remains one of the great mysteries of modern neuroscience. We spend nearly one-third
of our lives asleep, but the function of sleep still
is not known. Fortunately, over the last few
years researchers have made great headway in
understanding some of the brain circuitry that
controls wake-sleep states.
Scientists now recognize that sleep consists of several
di∑erent stages; that the choreography of a night’s sleep
involves the interplay of these stages, a process that depends
upon a complex switching mechanism; and that the sleep stages
are accompanied by daily rhythms in bodily hormones, body
temperature and other functions.
Sleep disorders are among the nation’s most common
health problems, a∑ecting up to 70 million people, most of
whom are undiagnosed and untreated. These disorders are one
of the least recognized sources of disease, disability and even
death, costing an estimated $100 billion annually in lost productivity, medical bills and industrial accidents. Research holds

the promise for devising new treatments to allow millions of
people to get a good night’s sleep.

The stu≈ of sleep
Sleep appears to be a passive and restful time when the brain is
less active. In fact, this state actually involves a highly active
and well-scripted interplay of brain circuits to produce the
stages of sleeping.
The stages of sleep were discovered in the 1950s in experiments examining the human brain waves or electroencephalogram (EEG) during sleep. Researchers also measured movements of the eyes and the limbs during sleep. They found that
over the course of the first hour or so of sleep each night, the
brain progresses through a series of stages during which the
brain waves progressively slow down. The period of slow wave
sleep is accompanied by relaxation of the muscles and the eyes.
Heart rate, blood pressure and body temperature all fall. If
awakened at this time, most people recall only a feeling or
image, not an active dream.

SLEEP PATTERNS. During a night of sleep, the brain waves of a young adult recorded by the electroencephalogram (EEG) gradually slow down and
become larger as the individual passes into deeper stages of slow wave sleep. After about an hour, the brain re-emerges through the same series of
stages, and there is usually a brief period of REM sleep (on dark areas of graph), during which the EEG is similar to wakefulness. The body is completely relaxed, the person is deeply unresponsive and usually is dreaming. The cycle repeats over the course of the night, with more REM sleep,
and less time spent in the deeper stages of slow wave sleep as the night progresses.

Awake
Awake

Stage 1

Stage 1

Stage 2

Stage 2

Stage 3
Stage 3
Stage 4
Stage 4
1

22

2

3

4

6

7

Hours